Clusterin is a sulfated glycoprotein, which is expressed in almost all cells. Its level in benign prostate is relatively low. Prostate cancer cells express more clusterin. The intensity immunohistochemical staining for clusterin in prostate cancer tissues correlates with the Gleason scores. Our recent results have demonstrated that clusterin is a novel antiapoptotic mediator in prostate cancer. The objective of the present application is to translate these laboratory observations into clinical settings. We propose to establish its utility as a prognostic marker in prostate cancer. Our hypothesis is that the level of clusterin expression is associated with resistance to apoptosis in prostate cancer cells, thus may serve as a prognostic marker. Four specific aims are proposed. Specific Aim 1 will manipulate the level of clusterin expression in human established prostate cancer cells, LNCaP, by our newly developed retrovirus gene transfer technique. We propose to inoculate 50 percent clusterin over-expressed cells (GFP) and 50 percent wild type LNCaP cells into orthotopic sites of nude mice. Results will be compared with that from the control tumors in which empty vector-GFP transfected cells (50 percent) will be mixed with wild type (50 percent). Specific Aim 2 will be a study to predict tumor development in high grade PIN. Needle biopsy specimens, containing high grade PIN, will be used for immunohistochemical staining for clusterin. In high-grade PIN specimens, we attempt to correlate the level of clusterin and bcl-2 expression with those that later developed prostate cancer. Specific Aim 3 is also a retrospective study in which prostatic tissues obtained from archival specimens will be used. Prostatectomy patients with an undetectable serum PSA will be selected for the study. The level of clusterin and bcl-2 expression in each case will be correlated with the Gleason grade. A rise in serum PSA will be considered as tumor recurrence. Specific Aim 4 will be a prospective study, in which clusterin levels in serum specimens, along with PSA and PAP, will be determined in prostate cancer patients who were diagnosed of having metastatic disease and receiving hormonal therapy. A rise in serum PSA, PAP, or clusterin will be used as an indication of failure to androgen ablation therapy. Results will be analyzed to determine if serum clusterin levels can be used, along with serum PSA and PAP, to predict endocrine treatment failure.